Definition

A trispecific T-cell enabler targeting the human tumor-associated antigen (TAA) prostate-specific membrane antigen (PSMA; FOLH1), the co-stimulatory receptor 4-1BB (CD137; tumor necrosis factor receptor superfamily member 9; TNFRSF9) and human serum albumin (HSA), with potential immunostimulating and antineoplastic activities. Upon administration, CD137/PSMA/HSA trispecific-targeting agent CB307 simultaneously targets and binds to 4-1BB, which is expressed on a variety of leukocyte subsets including activated T lymphocytes, and PSMA expressed on tumor cells. The simultaneous binding to PSMA enables clustering of 4-1BB and thereby allows for conditional stimulation of 4-1BB signaling within the tumor microenvironment (TME) only upon binding to PSMA on tumor cells. 4-1BB activation results in T-cell stimulation and enhances T-lymphocyte-mediated anti-tumor immune response against the PSMA-expressing tumor cells. PSMA is overexpressed on the surface of metastatic and hormone-refractory prostate tumor cells. 4-1BB, a surface glycoprotein of the tumor necrosis factor receptor superfamily, is an inducible costimulatory receptor that plays a key role in T-cell proliferation, survival and cytolytic activity. The albumin-binding domain targets and binds to HSA thereby extending the serum half-life of CB307. The conditional activation of 4-1BB signaling prevents systemic T-cell activation and lowers systemic toxicity.